Ted Cizadlo

The cerebellum plays a role in conscious episodic memory retrieval.

The cerebellum has traditionally been considered to be primarily dedicated to motor functions. Its phylogenetic development and connectivity suggest, however, that it also may play a role in cognitive processes in the human brain. In order to examine a potential cognitive role for the cerebellum in human beings, a positron emission tomography (PET) study was conducted during a “pure thought experiment”: subjects intentionally recalled a specific past personal experience (consciously retrieved episodic memory). Since there was no motor or sensory input or output, the design eliminated the possibility that cerebellar changes in blood flow were due to motor activity. During silent recall of a consciously retrieved episodic memory, activations were observed in the right lateral cerebellum, left medial dorsal thalamus, medial and left orbital frontal cortex, anterior cingulate, and a left parietal region. These activations confirm a cognitive role for the cerebellum, which may participate in an interactive cortical‐cerebellar network that initiates and monitors the conscious retrieval of episodic memory. Hum. Brain Mapping 8:226–234, 1999.

II. PET Studies of Memory: Novel versus Practiced Free Recall of Word Lists

Positron emission tomography (PET) with the tracer H215O was used to measure regional cerebral blood flow in 13 healthy volunteers while they engaged in free recall of 15-item word lists from the Rey Auditory Verbal Learning task. The study was designed so that recall of well-practiced versus novel material could be compared. One week before the PET study, subjects were trained to perfect recall of List A, while they were exposed to list B only 60 s prior to PET data acquisition. As in the companion study of free recall of complex narratives, we observed that practice tended to decrease the size of activations in regions involved in the memory component of the task; we also observed that the novel recall task produced greater activation in left frontal regions, probably due to active encoding. A commonality of other regions observed in this pair of studies, as well as other studies of memory in the literature, suggests that the human brain may contain a distributed multinodal general memory system. Nodes on this network include the frontal, parietal, and temporal cortices, the thalamus, the anterior and posterior cingulate, the precuneus, and the cerebellum. There appears to be a commonality of components across tasks (e.g., retrieval, encoding) that is independent of content, as well as differentiation of some components that may be content-specific or tasks-specific. In addition, these results support a significant role for the cerebellum in cognitive functions such as memory.

Functional MRI statistical software packages: a comparative analysis.

Currently, there are many choices of software packages for the analysis of fMRI data, each offering many options. Since no one package can meet the needs of all fMRI laboratories, it is helpful to know what each package offers. Several software programs were evaluated for comparison of their documentation, ease of learning and use, referencing, data input steps required, types of statistical methods offered, and output choices. The functionality of each package was detailed and discussed. AFNI 2.01, SPM96, Stimulate 5.0, MEDIMAX 2.01, and FIT were tested. FIASCO, Yale, and MEDx 2.0 were described but not tested. A description of each package is provided. Hum. Brain Mapping 6:73–84, 1998.

Tests for Comparing Images Based on Randomization and Permutation Methods

Tests comparing image sets can play a critical role in PET research, providing a yes-no answer to the question “Are two image sets different?” The statistical goal is to determine how often observed differences would occur by chance alone. We examined randomization methods to provide several omnibus test for PET images and compared these tests with two currently used methods. In the first series of analyses, normally distributed image data were simulated fulfilling the requirements of standard statistical tests. These analyses generated power estimates and compared the various test statistics under optimal conditions. Varying whether the standard deviations were local or pooled estimates provided an assessment of a distinguishing feature between the SPM and Montreal methods. In a second series of analyses, we more closely simulated current PET acquisition and analysis techniques. Finally, PET images from normal subjects were used as an example of randomization. Randomization proved to be a highly flexible and powerful statistical procedure. Furthermore, the randomization test does not require extensive and unrealistic statistical assumptions made by standard procedures currently in use.

Normalizing counts and cerebral blood flow intensity in functional imaging studies of the human brain.

Image intensity normalization is frequently applied to eliminate or adjust for subject or injection global blood flow (gCBF) and other sources of nuisance variation. Normalization has several other positive effects on the analysis of PET images. However, the choice of an intensity normalization technique affects the statistical and psychometric properties of the image data. We compared three normalization procedures, the ratio approach (regional (r)CBF/gCBF), histogram equalization, and ANCOVA, on both PET count and flow data sets. The ratio method presents the proportional increase of regions, the histogram equalization method offers the relative ranking of intensities over the image, and the ANCOVA method provides statistical deviations from an expected linear model of regional values from the subjects gCBF. The original study used 33 normal subjects in a standard subtraction paradigm. The normalization methods were evaluated on their ability to remove extraneous error variation, induce homogeneity of intersubject variation, and remove unwanted dependencies. In general, the normalization modified the subtraction image more than the individual condition images. All three methods worked well at removing the dependency of rCBF on gCBF in count and flow images. For count data, the three methods also reduced the amount of error variation equally well, improving the signal to noise ratio. For flow data, the histogram equalization and ratio methods worked best at reducing statistical error. All three methods dramatically stabilized the variance over the image.

Sample Size and Statistical Power in [15O]H2O Studies of Human Cognition:

Determining the appropriate sample size is a crucial component of positron emission tomography (PET) studies. Power calculations, the traditional method for determining sample size, were developed for hypothesis-testing approaches to data analysis. This method for determining sample size is challenged by the complexities of PET data analysis: use of exploratory analysis strategies, search for multiple correlated nodes on interlinked networks, and analysis of large numbers of pixels that may have correlated values due to both anatomical and functional dependence. We examine the effects of variable sample size in a study of human memory, comparing large (n = 33), medium (n = 16,17), small (n = 11, 11, 11), and very small (n = 6, 6, 7, 7, 7) samples. Results from the large sample are assumed to be the “gold standard.” The primary criterion for assessing sample size is replicability. This is evaluated using a hierarchically ordered group of parameters: pattern of peaks, location of peaks, number of peaks, size (volume) of peaks, and intensity of the associated t (or z) statistic. As sample size decreases, false negatives begin to appear, with some loss of pattern and peak detection; there is no corresponding increase in false positives. The results suggest that good replicability occurs with a sample size of 10–20 subjects in studies of human cognition that use paired subtraction comparisons of single experimental/baseline conditions with blood flow differences ranging from 4 to 13%.

Abnormalities in midline attentional circuitry in schizophrenia: evidence from magnetic resonance and positron emission tomography.

The syndrome of schizophrenia presents with a complex array of symptoms that are difficult to explain at the neural level. Data collected using magnetic resonance (MR) and positron emission tomography (PET) suggest that this complex array could occur as a consequence of misconnections and mismatches in midline circuitry that is reticular-thalamic-cingulate-cortical. MR studies have shown a variety of abnormalities, including callosal agenesis, cavum septi pellucidi, decreased thalamic size, decreased frontal size, and changes in signal intensity in white matter tracts between the thalamus and the frontal cortex. PET studies using a dichotic listening paradigm suggest that patients suffering from schizophrenia have brain blood flow abnormalities consistent with a difficulty in focusing or shifting attention, which may reflect the functional substrate of the anatomic abnormalities.

Image registration issues in the analysis of multiple injection 15O H2O PET studies: BRAINFIT

Spatial registration of functional and structural data is a vital first step in the regional analysis of images obtained from functional imaging techniques. We present a set of procedures that produce accurate, objective, and robust registrations between PET and MR images that are highly automated and user-friendly. These techniques have been shown to be both reliable and valid. Because the method is automated and therefore efficient, each injection of the PET experiment can be individually fit to overcome errors introduced because of subject movement between PET injections.

Landmark-based registration and measurement of magnetic resonance images: a reliability study.

We report a magnetic resonance imaging (MRI) study in a large number of subjects that examines various analytic techniques for anatomical landmark information. The initial issue involved interrater reliability in locating landmarks along the midsagittal plane. Another issue dealt with using landmarks to register (linear) individual scans for subsequent analyses or more sophisticated registration techniques. We next explore the use of interlandmark distances as indices of brain size. Twenty-seven landmarks were chosen from the midsagittal slice of 101 abnormal subjects. Interrater reliability estimates on a subset of the scans were excellent overall. Rotating to anterior-posterior commissure points was the best of the tested two-point registrations, although an average angular rotation was better. Reliability and validity for landmark-derived measures of size were excellent. Landmark-based analyses offer opportunities to explore shape and size questions, although they are not appropriate for addressing all questions. Under specific conditions, landmark data can be generated quickly and accurately.

Multi-center N400 ERP consistency using a primed and unprimed word paradigm

A word priming paradigm involving primed, unprimed, and non-word experimental conditions was used to elicit event-related potentials (ERPs) in normal, young adult males in identically equipped electrophysiology laboratories located in 6 different cities in the USA. Analyses of the average amplitude of a specified latency window containing the N400, the N400 peak amplitude, or the latency of the N400 peak amplitude found no differences among laboratory locations. The shape of the N400 ERP wave form was also found to be highly correlated across laboratory sites for each experimental condition. Comparison of the data with analogous word priming paradigms revealed similar patterns for the N400 components and response times in both the primed and unprimed experimental conditions. These findings suggest that the data from all 6 laboratory locations are consistent with each other and are congruous with those found in other N400 studies and will permit pooling of subject data for future research.